PEG sTNF-RI
Etanercept (Enbrel®)
Infliximab (Remicade™)
D2E7

POS-390 Non-Immunogenicity of a PEGylated Soluble Tumor Necrosis Factor Type I (PEG sTNF-RI [p55]). Davis M, Frazier J, Martin S, and Edwards III C. California.

A prior formulation of the soluble p55 TNF receptor coupled to polyethylene glycol [r-metHuTNFbp PEGylated dimer (TNFbp)] demonstrated clinical efficacy but was not suitable for a chronic indication due to the development antibodies upon multiple dosing which resulted in increased clearance of the drug. PEG sTNF-RI is a second generation molecule where the antigenic epitopes of TNFbp were removed. It has been shown in adjuvant arthritis models to be non-immunogenic with multiple SC dosing. The purpose of the phase I, multicenter, randomized, double-blind, placebo-controlled trial was to evaluate the safety and immunogenicity of PEG sTNF-RI in patients with moderate to severe rheumatoid arthritis. Patients received PEG sTNF-RI (100, 300, or 600 mg/kg) in one of the following schedules.

Schedule 1: (weekly) a single dose of PEG sTNF-RI or placebo followed 6 weeks later by weekly dosing for 3 weeks (4 doses total)
Schedule 2: (every other week) a single dose of PEG sTNF-RI or placebo every other week for 6 weeks (3 doses total)

An additional group received a single dose of 1000 mg/kg PEG sTNF-RI on day 1 only. 8-10 subjects participated in each treatment group. Levels of anti-sTNF-RI immunoglobulin-G (IgG) and immunoglobulin-M (IgM) antibodies were assessed.

Results: Of the 67 patients receiving PEG sTNF-RI treatment, 4 showed seroreactivity; 100 mg/kg (n=1), 600 mg/kg weekly (n=2), and 600 mg/kg every other week (n=1). No time- or dose-dependency was apparent. By study end, only one subject was considered to be still seroreactive (pt 416, 600 mg/kg weekly); the others were sero-negative for 3 to 8 weeks prior to the end of the study. The seroreative samples were tested for antibody specificity. Patient 416 had a non-specific IgG seroreactive response towards 4 domain E. coli derived sTNF-RI and IL-1ra (post:pre OD titer = 2.36 by day 64) and towards 2.6 domain E. coli sTNF-RI and PEG sTNF-RI (post:pre OD titer = 2.45 by day 64). No neutralizing antibodies to PEG sTNF-RI were found in serum samples from sereoreactive patients.

These date provide evidence that treatment with PEG sTNF-RI with doses ranging from 100-1000 mg/kg was non-immunogenic, thereby warranting the continuation of future clinical trials.

Editorial Comments: This is another TNF inhibitor that shows promise for clinical use in RA. Whereas etanercept (Enbrel^®) is a soluble dimeric p75 TNF receptor, this is a monomeric p55TNF receptor.

OP-052 A Phase III Trial of Etanercept vs Methotrexate (MTX) in Early Rheumatoid Arthritis (Enbrel^® ERA Trial). Martin R, Ruderman E, Fleischmann R, Moreland L, Schiff M, Bathon J, Spencer-Green G, and Finck B. Chicago, Misouri, Texas, Alabama, Colorado, Maryland, Washington.

These data were essentially the same as those presented at the American College of Rheuamtology meetings in Boston in November 1999. (review summary)

The objective of this analysis was to determine the long-term safety and efficacy of etanercept in adult rheumatoid arthritis (RA) patients. 713 patients were followed for up to 43 months, totaling 1251 patient years (553 for 12 mos, 500 for 18 mos, 373 for 24 mos, 139 for 30 mos, and 53 for 36-43 mos).

Initial median tender and swollen joint counts of 30 and 25, respectively, declined to 8 and 10 by 3 months and 4 and 5 by 30 months. By 30 months, 28% of patients had zero tender joints, 27% of patients had zero swollen joints, and 18% of patients had a zero HAQ disability index. Of the 383 patients on corticosteroids, 56% decreased their dose, 26% discontinued use, and 9% increased their dose. Ten malignancies of varying type were reported and the frequency was not greater than that expected (11.5) for the general population. The rate of occurrence of adverse events including headache, rash, nausea, rhinitis, diarrhea, and infections in patients receiving etanercept was not significantly different than the rate observed in patients receiving placebo. Of 43% of patients who had injection site reactions, less than 0.5% withdrew.

These data indicate that etanercept use up to 43 months is well tolerated, has no cumulative toxicity, and has a rapid and sustained clinical response.

Editorial Comments: Although there is theoretical concern for enhanced rates of malignancy and infection in patients treated long-term with TNF inhibitors, these long-term data do not bear this out. Patients in clinical trials are carefully selected, however, and may not always reflect what happens in the general population.

OP-005 Sustained Clinical Benefit and Arrest of Radiographic Joint Damage in Patients with Active Rheumatoid Arthritis Treated with Infliximab along with Methotrexate.RN Maini, DMFM van der Heijde, P Emery et al. The ATTRACT Investigators. London, UK.

These data were essentially the same as those presented at the American College of Rheuamtology meetings in Boston in November 1999. (review summary) These are important data showing the disease modifying properties of infliximab in combination with methotrexate.

POS-370 One Year Treatment Results of the Fully Human Anti-TNF Antibody D2E7 in Combination with Methotrexate in Active Rheumatoid Arthritis (RA). S Simianer, R Rau, S Wassenberg, E Kroot, P van Riel, L vande Putte, J Wastlhuber, M Schattenkirchner, C Allaart, F Breedveld, H Fenner, E Theophil, J Kempeni, H Kupper. Germany, The Netherlands, Switzerland.

This study was designed to evaluate the safety and efficacy of D2E7 in combination with methotrexate (MTX) in patients who have had inadequate responses to MTX. 54 patients with rheumatoid arthritis (RA) with disease activity scores (DAS) of >3.2 on a stable dose of methotrexate (7.5 to 25 mg/week) were randomized to one of three treatment groups: 1 mg/kg D2E7 subcutaneously (sc), 1 mg/kg D2E7 intravenously (iv), or placebo (sc or iv). A second injection was given when the response to the first faded, but not sooner than 4 weeks after the first injection. At ~week 8, all patients were given a third injection of D2E7 1 mg/kg (sc) in addition to their methotrexate. Three additional injections were given, mostly biweekly. Patients subsequently received D2E7 in an open label protocol "according to their response status". The median time interval between receipt of first randomised medication and receipt of first open label sc medication was 54 days.

Results: The initial double-blind phase demonstrated that both D2E7 (sc and iv) resulted rapid and comparable efficacy when compared to placebo for tender joint count (TJC), swollen joint count (SJC), C- Reactive Protein CRP), and patients assessment of disease activity. Data for the open-label phase (n=50) showed a clinically significant response by EULAR and ACR 20 criteria was achieved at 6 and 12 months in >69% of patients. Clinically significant reductions, ~60%, in TJC and SJC were achieved.

Editorial Comments: D2E7 is a fully human antibody directed against tumor necrosis factor-athat has been shown, as monotherapy, to reduce the signs and symptoms of RA and to slow radiographic disease progression (see 1999 American College of Rheumatology highlights). The current study indicates that D2E7 has therapeutic benefit in RA patients who have failed, or who have had inadequate responses to, methotrexate. These results are similar to those previously reported for etanercept (soluble p75 TNF receptor) and infliximab (chimeric mouse-human anti-TNF antibody).

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